US9346743B2ActiveUtilityPatentIndex 27

Processes for the synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compounds

Assignee: ALBEMARLE CORPPriority: Oct 15, 2012Filed: Oct 9, 2013Granted: May 24, 2016

Est. expiryOct 15, 2032(~6.3 yrs left)· nominal 20-yr term from priority

Inventors:THAKKAR AMIT ZEILER ANDREW G SKUFCA ANTHONY F SPRINGER JAMES J ASSINK BRYCE KELLY LOZANOV MARIO E

C07C 231/12C07C 253/14C07C 231/06C07C 255/60C07C 255/59C07C 237/44C07C 233/25C07C 231/02C07C 213/08Y02P20/55C07C 253/30

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Claims

Abstract

This invention provides a method for the synthesis of a 2-amino-4,6-dimethoxybenzamide and other benzamides of Compound I: wherein R 1 , R 2 , R 3 , and R 4 each independently represent a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxy; and wherein R 6 and R 7 each independently represent a hydrogen, a C 1 -C 6 alkyl, a protecting group, or a directing group.

Claims

exact text as granted — not AI-modified

The invention claimed is:

1. A process for producing at least one

wherein the process comprises:
(i) combining at least one

with at least one halogenating agent to produce at least one

(ii) combining the at least one Compound III with at least one cyanating agent to produce at least one

and;
(iii) combining the at least one Compound IV with at least one hydrating agent and/or at least one hydrating catalyst to produce the at least one Compound I,
wherein R 1 and R 5 each independently represent a hydrogen, a C 1 -C 6 alkyl, a hydroxy, or a C 1 -C 6 alkoxy;
wherein R 2 , R 3 , and R 4 each independently represent a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxy;
wherein R 6 and R 7 each independently represent a hydrogen, a C 1 -C 6 alkyl, a protecting group, or a directing group;
wherein X represents a halo moiety or a halo-like moiety;
wherein at least one of R 1 and R 5 represent a hydrogen; and
provided that in Compound II, R 7 represents a protecting group or a directing group, and either
(1) prior to step (ii), the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl, or
(2) prior to step (iii), the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl.

2. A process for producing at least one

wherein the process comprises:
(i) combining at least one

with at least one halogenating agent to produce at least one

(ii) combining the at least one Compound III with at least one cyanating agent to produce at least one

(iii) combining the at least one Compound IV with at least one first precipitating agent to precipitate the at least Compound IV; and
(iv) combining the at least one Compound IV with at least one hydrating agent and/or at least one hydrating catalyst to produce the at least one Compound I,
wherein R 1 and R 5 each independently represent a hydrogen, a C 1 -C 6 alkyl, a hydroxy, or a C 1 -C 6 alkoxy;
wherein R 2 , R 3 , and R 4 each independently represent a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxy;
wherein R 6 and R 7 each independently represent a hydrogen, a C 1 -C 6 alkyl, a protecting group, or a directing group;
wherein X represents a halo moiety or a halo-like moiety;
wherein at least one of R 1 and R 5 represent a hydrogen; and
provided that in Compound II, R 7 represents a protecting group or a directing group, and either
(1) prior to step (ii), the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl, or
(2) prior to step (iii), the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl.

3. The process according to claim 2 wherein prior to step (iv), the at least one Compound IV is combined with at least one second precipitating agent to precipitate the at least one Compound IV.

4. The process according to claim 2 wherein prior to step (ii), the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl.

5. The process according to claim 2 wherein prior to step (iii), the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R 7 is replaced with a hydrogen or a C 1 -C 6 alkyl.

6. The process according to claim 2 wherein the at least one Compound II is produced by a process comprising combining at least one

with at least one protecting agent to produce the at least one Compound II,
wherein R 6′ and R 7′ each independently represent a hydrogen or a C 1 -C 6 alkyl.

7. The process according to claim 2 wherein X represents Cl, Br, I, -OTf, -OMs, or -OTs.

8. The process according to claim 2 wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 5 represents a C 1 -C 6 alkoxy.

9. The process according to claim 2 wherein at least two of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a C 1 -C 6 alkoxy.

10. The process according to claim 2 wherein at least three of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a C 1 -C 6 alkoxy.

11. The process according to claim 2 wherein R 2 and R 4 each independently represent a C 1 -C 6 alkoxy, and R 1 and R 3 each represent a hydrogen.

12. The process according to claim 11 wherein the C 1 -C 6 alkoxy is a methoxy.

13. The process according to claim 6 , wherein the protecting agent comprises an anhydride.

14. The process according to claim 13 , wherein the anhydride is trifluoroacetic anhydride.

15. The process according claim 2 , wherein the at least one halogenating agent comprises DBDMH.

16. The process according to claim 2 , wherein the hydrating agent comprises water.

17. The process according to claim 2 , wherein the hydrating catalyst comprises at least one acid.

18. The process according to claim 17 , wherein the at least one acid is selected from trifluoroacetic, sulfuric and methanesulfonic acid.

19. The process according to claim 2 , further comprising conducting steps (i)-(iii) in a one-pot process reaction.

20. The process according to claim 2 , wherein in Compound II, R 2 and R 4 each independently represent a C 1 -C 6 alkoxy, R 1 and R 3 each represent a hydrogen, and R 7 represents trifluoroacetyl.

21. The process according to claim 2 , wherein the at least one halogenating agent comprises N-bromosuccinimide.

22. The process according to claim 2 , wherein the at least one cyanating agent comprises CuCN.

23. The process according to claim 2 , wherein the at least one cyanating agent comprises K 4 Fe(CN) 6 and CuI.

24. The process according to claim 2 , wherein Compound I is 2-amino-4,6-dimethoxybenzamide.

25. A process comprising:
(i) protecting 3,5-dimethoxyaniline with a protecting agent to produce a protected 3,5-dimethoxyaniline;
(ii) halogenating the protected 3,5-dimethoxyaniline with a halogenating agent to produce a halogenated protected 3,5-dimethoxyaniline;
(iii) cyanating the halogenated protected 3,5-dimethoxyaniline with a cyanating agent to produce a cyanated protected 3,5-dimethoxyaniline;
(iv) deprotecting the cyanated protected 3,5-dimethoxyaniline; and
(v) hydrating the precipitate comprising the cyanated 3,5-dimethoxyaniline to produce 2-amino-4,6-dimethoxybenzamide.

26. A process comprising:
(i) protecting 3,5-dimethoxyaniline with a protecting agent to produce a protected 3,5-dimethoxyaniline;
(ii) halogenating the protected 3,5-dimethoxyaniline with a halogenating agent to produce a halogenated protected 3,5-dimethoxyaniline;
(iii) cyanating the halogenated protected 3,5-dimethoxyaniline with a cyanating agent to produce a cyanated protected 3,5-dimethoxyaniline;
(iv) deprotecting the cyanated protected 3,5-dimethoxyaniline and inducing precipitation to produce a precipitate comprising the cyanated 3,5-dimethoxyaniline; and
(v) hydrating the precipitate comprising the cyanated 3,5-dimethoxyaniline to produce 2-amino-4,6-dimethoxybenzamide.

27. A process comprising:
(i) protecting 3,5-dimethoxyaniline with a protecting agent to produce a protected 3,5-dimethoxyaniline;
(ii) halogenating the protected 3,5-dimethoxyaniline with a halogenating agent to produce a halogenated protected 3,5-dimethoxyaniline;
(iii) cyanating the halogenated protected 3,5-dimethoxyaniline with a cyanating agent to produce a cyanated protected 3,5-dimethoxyaniline;
(iv) deprotecting the cyanated protected 3,5-dimethoxyaniline and inducing precipitation to produce a first precipitate comprising the cyanated 3,5-dimethoxyaniline;
(v) re-precipitating the first precipitate comprising the cyanated 3,5-dimethoxyaniline to produce a second precipitate comprising the cyanated 3,5-dimethoxyaniline; and
(vi) hydrating the second precipitate comprising the cyanated 3,5-dimethoxyaniline to produce 2-amino-4,6-di methoxybenzamide.

28. A process comprising:
(i) protecting a 3,5-dimethoxyaniline with a protecting agent to produce a protected 3,5-dimethoxyaniline;
(ii) halogenating the protected 3,5-dimethoxyaniline with a halogenating agent to produce a halogenated protected 3,5-dimethoxyaniline;
(iii) deprotecting the halogenated protected 3,5-dimethoxyaniline to produce a halogenated 3,5-dimethoxyaniline;
(iv) precipitating the halogenated 3,5-dimethoxyaniline;
(v) cyanating the halogenated 3,5-dimethoxyaniline with a cyanating agent to produce a cyanated 3,5-dimethoxyaniline;
(vi) precipitating the cyanated 3,5-dimethoxyaniline, and
(vii) hydrating the precipitated cyanated 3,5-dimethoxyaniline to produce 2-amino-4,6-dimethoxybenzamide.

29. The process according to claim 27 or claim 28 , wherein the protected 3,5-dimethoxyaniline is 3,5-dimethoxytrifluoroacetanilide.

30. The process according to claim 27 or claim 28 , wherein the halogenated protected 3,5-dimethoxyaniline comprises bromo-3,5-dimethoxytrifluoroacetanilide isomers.

31. The process according to claim 27 or claim 28 , wherein the cyanated protected 3,5-dimethoxyaniline comprises cyano-3,5-dimethoxytrifluoroacetanilide isomers.

32. The process according to claim 27 or claim 28 , wherein the protecting agent comprises an anhydride.

33. The process according to claim 32 , wherein the anhydride is trifluoroacetic anhydride.

34. The process according to claim 27 or claim 28 , wherein the protecting agent is an acid chloride.

35. The process according to claim 27 or claim 28 , wherein the halogenating agent comprises N-bromosuccinimide.

36. The process according to claim 27 or claim 28 , wherein the cyanating agent comprises CuCN.

37. The process according to claim 27 or claim 28 , wherein the cyanating agent comprises K 4 Fe(CN) 6 and CuI.

38. The process according to claim 27 or claim 28 , wherein the hydrating agent comprises water.

39. The process according claim 27 or claim 28 , wherein the hydrating catalyst comprises at least one acid selected from trifluoroacetic acid, sulfuric acid, and methanesulfonic acid.

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